Adding Hetrombopag to Cyclosporine a to Patients with Newly Diagnosed Transfusion-Dependent Non-Severe Aplastic Anemia-a Prospective Phase 2 Study

Abstract

Objective: To investigate the efficacy and safety of adding hetrombopag to cyclosporin A (CsA) in patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA).

Methods: This was a single center, prospective phase 2 study. Eligible patients were aged 18 years or older, were diagnosed as TD-NSAA within 6 months and treatment-naïve. Enrolled patients were treated with hetrombopag and CsA. Hetrombopag was started at 10mg/day with possible titration up to 15mg/day, and tapered gradually when the optimal response was achieved. CsA was given at 3-5mg/kg/d for at least 6 months, and tapered after the optimal response was reached. The primary endpoint was the overall response rate (ORR) and safety at 6 months. Patients who had been followed-up for at least 6 months were included in the analysis. A history cohort with compatible baseline characters treated with CsA alone were analyzed as control. The trial was registered with ClinicalTrails.gov NCT05018936.

Result: Between Oct 2021 to Oct 2022, 28 patients were enrolled, comprising 13 men and 15 women, median age 46(range: 18-81). The ORR was 68.2% at 6 months. The most frequently reported adverse events were gastrointestinal discomfort grade 1 or 2. No grade 3 or 4 treatment-emergent adverse events were reported. There were 30 patients enrolled in the history control cohort with compatible baseline characters including age, sex ratio, complete blood cell count (P>0.05). After a median follow-up of 15 (range: 9-22) vs 16 (range:9-24) months(P>0.05), the ORR at 3, 6 months and the end of follow-up were 57.1% vs 16.7% (P=0.001), 68.2% vs 30.0% (P=0.006) and 90.9% vs 46.6%(P<0.001) in hetrombopag plus CsA group and CsA alone group, respectively. The complete response rate (CRR) at 3, 6 months and the end of follow-up were 10.7% vs 0% (P=0.068), 22.7% vs 10.0% (P=0.217) and 36.4% vs 16.6% (P=0.109) in both groups, respectively. Adverse effects were reported in 13 (46.4%) patients in hetrombopag plus CsA group and 15 (50%) patients of CsA alone group (P>0.05). 1 (3.6%) vs 8 (26.6%) patient relapsed (P=0.038) at 6 month in both groups. Clone evolution were noticed in no patients in hetrombopag plus CsA group and 2 (6.7%) patients in CsA alone group at 12 and15 months, respectively (P=0.225).

Conclusion: Adding hetrombopag to CsA can improve the ORR for newly diagnosed TD-NSAA, with good tolerance and lower relapse rate.

Keywords: Transfusion-dependent aplastic anemia, Hetrombopag, Cyclosporin A, efficacy, relapse.